Seeinstructions): Smallpox, though eradicated as a global health risk in 1980, has the potential of becoming one of the world's most dangerous weapons of mass destruction The Western Reserve strain of vaccinia virus (W) is the most accepted model used to study the biology of smallpox. W has been used extensively via multiple routes of infection to examine the immunopathogenesis of W in vivo. Although it is widely accepted that the lung is the primary route of clinical W infection there are very few reports examining the local immune response to intrapulmonary W infection. As such, the immunopathogenesis of pulmonary W is largely unknown. Dendritic cells (DC)s are required for initiating immune responses to any antigen or pathogen. Human and murine DCs may be divided into two major groups: myeloid DCs (mDC) and plasmacytoid DCs (pDC). While mDC have major roles in the induction of cellular (T cell-mediated) immune responses, recent reports highlight a nearly unique role for DCs in general and pDCs, in particular, in viral infections. Due to the specific characteristics of lung DCs, reports of DCs-induced antiviral immunity in non-pulmonary tissues may not be applicable to the lungs infected with W. Since the lung is the initial site of infection prior to systemic dissemination and the lung immune environment is unique, pulmonary DC-induced immunity may also be the gateway to regulate systemic anti-W responses. However, the direct role of lung DCs, in local anti-W immunity has not been studied, and the effect of initial local W immunity on systemic infection is unknown. This proposal tests the hypothesis that lung dendritic cells in general, and pDCs in particular, regulate the immune response to intrapulmonary W infection and established allergic lung disease by examining the following specific aims: Aim 1. To determine the role of specific pulmonary antigen presenting cell populations in anti-W immunity. Aim 2. To determine the role of pre-existing acute and chronic atopic lung disease on local vaccinia immunity. W will be instilled into the lungs of mice with acute atopic allergic lung inflammation, or animals with chronic pulmonary allergy. The effects of W inoculation on the immunology of allergic lung disease will be assessed, including dendritic cell-induced anti-W immunity. RELEVANCE (Seeinstructions): Smallpox remains a threat for bioterrorism, but the immune response in the lung, its natural portal of entry are largely unknown. This application will determine the immune response in the lung to W, the model for smallpox, and examine the effects of underlying allergic lung disease on this response.